Warning

Use only under the supervision of a qualified clinician experienced in the use of cytotoxic therapy.1 Use only when adequate treatment facilities for appropriate management of therapy and complications are available.1

Dose-related bone marrow suppression may result in infection and/or bleeding.1 Anemia may be cumulative and may require transfusion support.1

Introduction

Uses for Carboplatin

Carboplatin and cisplatin appear to have similar efficacy in the treatment of platinum-responsive ovarian tumors,15910111260137184185 lung cancers†,1829121137 and certain head and neck cancers†;17137 carboplatin is less effective than cisplatin in certain testicular cancers.2478137193

Because carboplatin and cisplatin have different toxicity profiles,123458910111268 carboplatin may be effective in patients with platinum-responsive tumors who are unable to tolerate cisplatin because of renal impairment, refractory nausea, hearing impairment, or neuropathy;440137 cisplatin may be preferred in patients with decreased bone marrow reserve or high risk of sepsis or those requiring anticoagulation therapy.10137

Ovarian Cancer

Combination therapy with platinum-containing agent (carboplatin or cisplatin) and paclitaxel† is the preferred regimen for initial treatment of advanced epithelial ovarian cancer; therapy with platinum-containing agent and paclitaxel is superior to therapy with platinum-containing agent and cyclophosphamide.92960137139147 Carboplatin is as effective as but less toxic than cisplatin when used in combination with paclitaxel184185 or cyclophosphamide.1011

Carboplatin in combination with docetaxel has been used for the first-line treatment of ovarian cancer† and has demonstrated similar efficacy and a different tolerability profile (i.e., more hematologic toxicity but less neurotoxicity) compared with carboplatin in combination with paclitaxel.196

Has been used as a single agent in the first-line treatment of advanced ovarian cancer†.929 Role remains to be established, but some clinicians consider single-agent carboplatin a reasonable option.29137187

Used alone as second-line therapy for palliative treatment of recurrent ovarian cancer in patients with platinum-sensitive disease;129 nonplatinum-based regimens generally preferred for retreatment of patients with platinum-refractory disease.296072

Being studied for use in combination regimens for second-line treatment of advanced ovarian epithelial cancer†.9188189

Has been used alone or in combination therapy for adjuvant treatment of early-stage ovarian cancer†.9179180 Survival benefit may be limited to patients whose disease is associated with poorer prognosis.137179

Lung Cancer

Treatment of small cell lung cancer† as a component of combination regimens.34181920297576

Cervical Cancer

Role in the treatment of cervical cancer† remains to be established.157166 Current evidence supports use of cisplatin in chemotherapy regimens given concurrently with radiation therapy in patients with locally advanced cervical cancer; similar benefit from carboplatin-containing chemotherapy cannot be assumed.157166

An active agent in the treatment of metastatic or recurrent cervical cancer†.29163164165 May be considered an alternative to cisplatin, particularly in patients with nephrotoxicity or neurotoxicity caused by advanced cervical tumor who are not candidates for cisplatin therapy.163164165

Head and Neck Cancer

May be useful in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck†.3451516172941128135200

Wilms’ Tumor

Brain Tumors

Has been used for palliative treatment of various primary brain tumors†.329

Has shown activity in the treatment of progressive or recurrent low-grade gliomas in children†;295657 responses observed in adults with recurrent glioma, including those who had received previous chemotherapy with nitrosoureas.29170171

Has shown activity in the treatment of recurrent medulloblastoma†.56130

Combination therapy with platinum-containing agent (cisplatin or carboplatin) and etoposide is used for treatment of intracranial germ cell tumors†.29169176

Neuroblastoma

Testicular Cancer

Cisplatin-based regimen (i.e., cisplatin/etoposide or cisplatin/etoposide/bleomycin) is more effective than carboplatin-based regimen (i.e., carboplatin/etoposide or carboplatin/etoposide/bleomycin) for initial treatment of good-prognosis metastatic nonseminomatous germ cell tumor; generally reserve use of carboplatin regimen for patients who do not tolerate or who refuse cisplatin.2478137193

Limited data suggest that high-dose carboplatin and etoposide may be effective in some patients with relapsed or refractory germ cell tumors†.233059

Bladder Cancer

Has been substituted as a less toxic alternative to cisplatin in the treatment of advanced bladder cancer† in some patients receiving combination chemotherapy.143146

Combination therapy with paclitaxel followed by carboplatin is being studied in patients with advanced bladder cancer, including those with abnormal renal function.97131168190

Retinoblastoma

Has been used in combination with etoposide in a limited number of children† with recurrent or progressive retinoblastoma†.102106

Breast Cancer

Has been used in a limited number of patients with metastatic breast cancer†.199

Endometrial Cancer

Being studied in the treatment of advanced or recurrent endometrial cancer†.195

Carboplatin Dosage and Administration

General

Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Carboplatin is considered a moderate antiemetic risk antineoplastic (i.e., 30–90% incidence of emesis without antiemetics).201 Antiemetic therapy (e.g., a 5-HT3 receptor antagonist and dexamethasone) is recommended to prevent nausea and vomiting.201 (See Emetogenic Effects under Cautions.)

Resulting solutions can be further diluted to concentrations as low as 0.5 mg/mL with 5% dextrose injection or 0.9% sodium chloride injection.b

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use.b

Dilution

May be diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration as low as 0.5 mg/mL.1

Rate of Administration

Administer by IV infusion over a period of ≥15 minutes;1241013252742 also has been administered by continuous IV infusion over 24 hours.123

Dosage

Base dosage on the clinical, renal, and hematologic response and tolerance of the patient in order to obtain optimum therapeutic response with minimum adverse effects.11011

Initial dosage can be based on body surface area, but dosage may be more accurately calculated using formula dosing methods based on the patient’s renal function.1818283848593107108137 (See Methods for Individualization of Dosage under Dosage and Administration.)

When used as a component of a multiple-drug regimen, consult published protocols for the dosage of each chemotherapeutic agent and the method and sequence of administration.

Adults

Ovarian Cancer

Initial Therapy for Advanced (Stage III and IV) Ovarian Carcinoma

IV

Initially, 300 mg/m2 given in combination with cyclophosphamide.11011 Adjust subsequent dosage according to the patient’s hematologic tolerance of the previous dose (see Dosage Adjustment in the Treatment of Ovarian Cancer); do not administer doses until hematologic function is within acceptable limits.1

A course of carboplatin consists of single doses administered once every 4 weeks (or longer if delayed for hematologic toxicity) for a total of 6 cycles.11011697071

Secondary Treatment of Advanced Ovarian Cancer

IV

Initially, 360 mg/m2 as monotherapy.1 Administer drug once every 4 weeks (or longer if delayed for hematologic toxicity).1 Adjust subsequent dosage according to the patient’s hematologic tolerance of the previous dose (see Dosage Adjustment in the Treatment of Ovarian Cancer); do not administer doses until hematologic function is within acceptable limits.1137

Methods for Individualization of Dosage

Alternative methods for calculating initial carboplatin dosage have been suggested based on the patient’s pretreatment renal function or pretreatment renal function and desired platelet nadir.138818283848593107108

Calvert Formula

Calculation is based on the patient’s GFR (in mL/minute) and the target AUC (in mg/mL per minute).181828393137Dosage is calculated in mg, not mg/m2.1

A target AUC of 5 (range: 4–6) mg/mL per minute appears to provide the most appropriate dosage range for use of carboplatin alone in patients previously treated with chemotherapeutic agents.1828393

Actual Toxicity in Previously Treated Patients1828393

AUC (mg/mL x min)

Percentage of Patients with Grade 3 or 4 Thrombocytopenia

Percentage of Patients with Grade 3 or 4 Leukopenia

4–5

16%

13%

6–7

33%

34%

For patients who previously did not receive chemotherapy, a target AUC of 7 (range: 6–8) mg/mL per minute has been recommended when carboplatin is used alone.828393 Higher target AUCs (e.g., 7.5 mg/mL) also have been used (e.g., when carboplatin was used as a component of high-intensity dosing with paclitaxel and a hematopoietic agent for non-small cell lung carcinoma).121 Subsequent carboplatin dosage has been adjusted according to hematologic tolerance to the previous dose (e.g., reducing the dose by 25% for moderate to severe hematologic toxicity).121

Formula is not sufficiently accurate to determine dosage for children or for adults with severe renal impairment (i.e., GFR <20 mL/minute); therefore, do not use this formula in such patients.83 Consult specialized references for an alternative pediatric formula.8393119120

Chatelut (French) Formula

Method does not require determination of GFR.848593Dosage is calculated in mg, not mg/m2.8493

Renal Impairment

Incidence of severe leukopenia, neutropenia, or thrombocytopenia at these adjusted initial dosages is about 25%.1 Adjust subsequent dosage according to the patient’s hematologic tolerance to the previous dose.1 Experience in patients with Clcr <15 mL/minute is too limited to make dosage recommendations.1

Geriatric Patients

Use of dosing formulas incorporating estimates of GFR to determine dosage recommended in geriatric patients.1

Cautions for Carboplatin

Contraindications

History of sensitivity reactions to carboplatin or other platinum-containing compounds (e.g., cisplatin).1

Hematologic Effects

Myelosuppression appears to be most common and more severe in patients who received prior antineoplastic therapy (especially cisplatin-containing regimens), those concurrently receiving or having recently received other myelosuppressive drugs or radiation therapy, and those with renal impairment.13385366678283848593101121137 Patients with poor performance status also appear to be at increased risk for severe leukopenia and thrombocytopenia.1 (See Interactions.)

At usual dosages, thrombocytopenia is more common and pronounced than leukopenia.538293 Thrombocytopenia may be cumulative and occasionally require transfusions.121 Potential for infection.11011

Anemia may be severe or symptomatic (e.g., accompanied by asthenia).11011 Incidence appears to be cumulative.193121 Transfusions may be required, particularly in patients receiving prolonged (>6 cycles) therapy.1121137

Do not administer to patients with severe bone marrow depression or substantial bleeding.1 In patients who experience myelosuppression, withhold subsequent cycles until neutrophil counts are >2000/mm3 and platelet counts are >100,000/mm3.1

Emetogenic Effects

Carboplatin is classified as an antineoplastic agent of moderate emetic risk (i.e., 30–90% incidence of emesis without antiemetics).201 Acute vomiting episodes are most common in patients who received prior emetogenic antineoplastic regimens (especially cisplatin-containing regimens) and in those receiving other emetogenic agents concurrently.1201

Possible reduction in the incidence of nausea and vomiting when given as a 24-hour continuous IV infusion or IV in divided doses over 5 consecutive days rather than as a single IV infusion; however, efficacy of these schedules not established.1

Pretreatment with antiemetics may reduce incidence and severity of emesis; rarely, nausea and vomiting may be refractory to antiemetic therapy.1393103136201 For prevention of acute emesis, ASCO recommends a 2-drug antiemetic regimen consisting of a type 3 serotonin (5-HT3) receptor antagonist and dexamethasone given before carboplatin.201

For the prevention of delayed emesis following administration of carboplatin, ASCO recommends single-agent therapy with dexamethasone or a 5-HT3 receptor antagonist.201

Optimal use of antiemetics for prevention of acute and delayed emesis during early courses of therapy is the most important means for preventing anticipatory vomiting; behavioral modification, hypnosis, and drug therapy (e.g., benzodiazepine with or without conventional antiemetics) also may be useful.136201

Ocular Effects

Loss of vision (sometimes complete for light and colors) reported in patients receiving higher than usually recommended dosages; improvement and/or total recovery of vision has occurred within weeks following drug discontinuance.131

Fetal/Neonatal Morbidity and Mortality

Sensitivity Reactions

Hypersensitivity Reactions

Prior exposure to other platinum-containing agents increases the risk for carboplatin-induced allergic reactions, including anaphylaxis.1

Exposure (e.g., industrial) to platinum-containing compounds can cause asthma and immediate and delayed hypersensitivity reactions;333693 consider the possibility that patients with a history of such exposure may be cross-sensitive to carboplatin.36

Observe closely for possible hypersensitivity reactions.161 Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of such reactions (e.g., antihistamines, epinephrine, oxygen, corticosteroids) should be readily available when carboplatin is administered.161

General Precautions

Mutagenicity and Carcinogenicity

Carcinogenic potential not fully studied; however, drugs with similar mechanisms of action and evidence of mutagenic effects have been reported to be carcinogenic.1 Secondary malignancies reported in patients receiving carboplatin in combination with other agents.1

Renal Effects

Nephrotoxicity is less common and severe than that associated with cisplatin; concomitant IV hydration and diuresis generally not necessary.110112427379293 However, consider the possibility that nephrotoxicity may be potentiated by other nephrotoxic drugs.1 (See Interactions.)

Lactation

Pediatric Use

Limited experience in the treatment of germ cell tumors in adolescents ≥16 years of age,24 various brain tumors or neuroblastoma in children 6 months to 19 years of age,2627285662 and Wilms’ tumor in children 2–15 years of age.667980

Adverse effects reported to date in children are similar to those reported in adults and include hematologic toxicity (principally thrombocytopenia),272856667980 adverse GI effects (e.g., nausea, vomiting),27285666 hypersensitivity reactions (e.g., urticaria, facial swelling, abdominal pain, coryza, cough),62 and hearing loss (particularly at higher than recommended doses in combination with other ototoxic agents).1

Geriatric Use

In clinical trials evaluating carboplatin as combination therapy for ovarian cancer, age was not found to be a factor for survival in patients ≥65 years of age relative to younger adults.1

Possible increased incidence of severe thrombocytopenia and carboplatin-induced peripheral neuropathy in adults ≥65 years of age compared with younger patients.1

Monitor carefully; manage dosage and time of administration to minimize additive toxic effects193137

Carboplatin Pharmacokinetics

Complex pharmacokinetics involve the parent compound as well as total platinum (protein-bound and nonprotein-bound platinum) and ultrafilterable platinum (carboplatin and nonprotein-bound carboplatin metabolites).12344344

Absorption

Bioavailability

Following intraperitoneal administration†, peak plasma concentrations of total platinum, free platinum, and carboplatin are attained within 2–4 hours following instillation.344347

Distribution

Extent

Widely distributed into body tissues and fluids, with highest concentrations in the kidney, liver, skin, and tumor tissue;34344 lower concentrations found in fat and brain.343 Also distributed into erythrocytes.4344

Not known whether carboplatin or its platinum-containing products cross the placenta or are distributed into milk.1

Plasma Protein Binding

Carboplatin is not bound to plasma proteins, but degrades to platinum-containing products which rapidly bind to protein.4549

<24% of platinum is bound to plasma proteins during the first 4 hours after IV administration of carboplatin; within 24 hours, 87% is protein bound.46

Elimination

Metabolism

Metabolic fate has not been completely elucidated.13456743 No evidence to date that the drug undergoes enzymatic biotransformation; the bidentate dicarboxylate ligands of carboplatin are believed to be displaced by water, forming positively charged platinum complexes that react with nucleophilic sites on DNA.13456743

Half-life

Special Populations

In patients with impaired renal function, renal clearance and total body clearance of platinum are reduced.343854 In patients undergoing hemodialysis, t½β values for total and ultrafilterable platinum are increased compared with values in individuals with normal renal function.4354

Actions

Appears to exert effects by binding to DNA, thereby inhibiting DNA synthesis;2345679293 effects are cycle-phase nonspecific.14 Antineoplastic activity may also involve other mechanisms.34592137

Must undergo activation before antineoplastic activity occurs.12345679293 Both carboplatin and cisplatin are activated by an initial aquation reaction,34592 but carboplatin is a more stable compound and is activated more slowly than cisplatin.13456792

Higher concentrations of carboplatin than cisplatin are required to produce equivalent levels of DNA binding.134567 At concentrations that produce equivalent levels of DNA binding, both drugs induce equal numbers of drug-DNA cross-links, resulting in equivalent lesions and biologic activity.134567 Antitumor activity of carboplatin in mice is comparable to or slightly less than that of cisplatin.3

Further study needed to fully elucidate the extent of cross-resistance between cisplatin and carboplatin.2 Although some cisplatin-refractory tumors may respond to carboplatin, a high degree of cross-resistance appears to occur between the drugs.3492

Advice to Patients

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy.1 Advise pregnant women of risk to the fetus.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

75. Ettinger DS. The place of ifosfamide in chemotherapy of small cell lung cancer: the Eastern Cooperative Oncology Group Experience and a selected literature update. Semin Oncol. 1995; 22(Suppl 2):23-7. http://www.ncbi.nlm.nih.gov/pubmed/7846538?dopt=AbstractPlus